The role of cytokines in immunological processes has now been recognized to be important and complex. A recent review article by Whicher et al., Clin. Chem. 36(7): 1269-1281 (1990), the disclosure of which is incorporated by reference herein, nicely summarizes what is known about the various cytokines and growth factors, including interleukins 1 through 8. Sources for these molecules, as well as their target cells are described. Of particular relevance to this disclosure are interleukin 4 ("IL-4" hereafter), and a cytokine not discussed in the review article, but know to the art, interleukin-9 ("IL-9" hereafter).
IL-4 is derived from T cells and mast cells, and targets T cells, B cells, macrophages/monocytes and mast cells. In particular, as Whicher points out at page 1274, IL-4 has a major role in the allergic response, following its release by activator TH.sub.2 cells. The IL-4 molecule is involved in "Ig switching", i.e., the change to production of different types of Ig by B cells. This cytokine influences a switch toward production of IgE and IgA. See Yokota et al., Immunol. Rev. 102: 137-187 (1988).
IL-4's involvement in the allergic response is discussed in some detail by Knight, Bio/Technology 8: 717-719 (1990), the disclosure of which is incorporated by reference. The reference discusses, inter alia, the possibility of "short-circuiting" the allergic response by administering a soluble receptor of IL-4 to an afflicted subject. Both natural and recombinant forms of the receptor are available, but the latter type cannot bind to cells because it lacks a portion of the complete molecule Nonetheless, it binds to the IL-4 molecule, preventing the stimulus leading to Ig switching in B cells.
This approach, i.e., that of using a soluble receptor for a cytokine so as to impact its normal effect, is demonstrated in the scientific literature. Fanslow, et al., Science 248: 739-741 (May 11, 1990) discuss the use of soluble IL-1 receptors, as well as antibodies which bind to this cytokine and suggests their use to mediate IL-1 related disorders. Smith, et al., Science 248 1019-1023 (May 25, 1990) discusses the role of soluble receptors for tumor necrosis factor (TNF) and potential value in therapeutic environments. The above referenced disclosures are incorporated by reference herein. In fact, soluble IL-1 receptor has been reported to inhibit rejection of heart transplants, and is suggested as being useful in treating diseases such as rheumatoid arthritis and multiple sclerosis where stimulation by IL-1 is involved. See Kolata, "Test Drug Blocks Rejection of New Hearts In Mice", New York Times, May 11, 1990.
Fairly recent work has identified a new member of the interleukin family, the molecule referred to by Hultner, et al., in Eur. J. Immunol. 20: 1413 (1990), as interleukin 9. This paper, the disclosure of which is incorporated by reference herein, sets forth research which shows, inter alia, that the molecules previously known as P40 (Uyttenhove, et al., PNAS 85: 6934 (1988)), and TCGFIII (Schmitt, et al., Eur. J. Immunol. 19: 2167 (1989)), as Well as by Yang, et al., Blood 74: 1990 (1989), and Renauld, et al., Cytokine 2: 9 (1990), are the same. All of the foregoing papers are incorporated by reference herein. This molecule has been shown to possess many properties, including the ability to support the growth of helper T cell clones and mucosal mast cells. The latter are known to be involved in regulation of type I hypersensitivity reactions.
Druez, et al., J. Immunol. 145: 2494-2499, Oct. 15, 1990, the disclosure of which is incorporated by reference, and U.S. Ser. No. 585,229, filed Sep. 19, 1990, the disclosure of which is incorporated by reference herein describe the discovery and isolation of a receptor for interleukin-9, referred to as IL9R.
The IL9-R molecule is a glycoprotein which is characterized by a molecular mass of about 64 kilodaltons. Upon treatment with N-glycosidase F, the glycoprotein is digested to a peptide having a molecular weight of about 54 kilodaltons. Apart from binding to IL-9, the receptor may also be characterized in terms of its sources, which include IL-9 dependent cell line TS1. However, the activity of IL-9 on various cell types (Uyttenhove et al., Proc. Natl. Acad. Sci. USA 85: 6934 (1988); Van Snick et al., J. Exp. Med. 169: 363 (1989), Simpson et al., Eur. J. Biochem. 183: 715 (1989); Schmitt et al., Eur. J. Immunol. 19: 2167 (1989); Yang et al., Blood 74: 1880 (1989), suggests additional sources as well.
It has now been found by the inventors that IL-9 plays an important role in potentiating the effect that IL-4 has on the stimulation of IgG and IgE productions. This discovery, together with the discovery of a receptor for the IL-9 molecule itself, paves the way for a method of reducing the production of IgE in a subject. It is this, as well as a method for stimulating IgG production both in vitro and in vivo, in addition to a method for evaluating efficacy of anti-allergic treatment as well as a method for monitoring chronic diseases where abnormal IgE production is a feature that are the subjects of this invention.